Project Summary Bipolar Disorder (BD) is a leading cause of disability, morbidity, and mortality worldwide. The high heritability of BD places offspring of parents with BD at an increased risk for developing BD and other psychiatric disorders such as Depression, ADHD, and Anxiety Disorders. By identifying abnormalities in the structure and function of neural circuitries important for emotion and emotional regulation processes aberrant in individuals with BD, neuroimaging studies of youth at risk for BD may identify biomarkers of pathophysiological processes of BD in as yet unaffected individuals which may be used for earlier diagnosis and treatment of BD. Since there are no multimodal or longitudinal neuroimaging studies in native space to date in healthy youth genetically at risk for developing BD, the relationships between white matter and functional abnormalities in these neural circuitries, and their relationships with symptoms that may predate BD onset, have yet to be elucidated. The objective of this proposal is thus to combine diffusion tensor imaging (DTI) and functional magnetic resonance imaging (fMRI) to identify neuroimaging biomarkers of risk for future BD by examining the white matter structure and function of neural circuitry supporting emotional regulation processes aberrant in BD. This will be accomplished both through a cross-sectional comparison of 30 healthy offspring of bipolar parents and 30 healthy offspring of healthy parents, as well as through a longitudinal analysis of the offspring of bipolar parents (follow-up: 1.5-2 years), to study structural-functional relationships in emotional regulation circuitries implicated in risk for BD. The first aim is to elucidate the relationships between white matter structure and function in prefrontal cortical and subcortical neural circuitry implicated in the pathophysiology of BD in at-risk youth. Functional connectivity analyses and Least Absolute Shrinkage and Selection Operator (LASSO) regression analyses will be used to identify relationships between the structure of white matter tracts important in emotion regulation circuitry (corpus callosum, anterior cingulum bundle, uncinate fasciculus, and superior longitudinal fasciculus) and activity within and functional connectivity between neural regions important in emotional regulation circuitry (amygdala, dorsolateral and ventrolateral prefrontal cortex, and anterior cingulate cortex) during a facial emotion processing task. The second aim is to determine relationships between structural and functional abnormalities in this circuitry and symptoms that predate the development of BD, namely anxiety, affect lability, depression, and mania. The third aim is to explore relationships among longitudinal changes in white matter structure, activity, functional connectivity, and symptom severity in BD at-risk youth. For the first time in the literature, using these multimodal neuroimaging methods to study youth at risk for BD both cross-sectionally and longitudinally will provide a more comprehensive understanding of the developmental trajectories predisposing to BD in at-risk youth. This will ultimately lead to improvements in earlier diagnostic accuracy and provide neural targets for therapeutic interventions in individuals suffering from, and at risk for developing, BD.